Association of circadian properties of temporal processing with rapid antidepressant response to wake and light therapy in bipolar disorder.

BACKGROUND: Temporal processing, crucial to guide behavior toward a goal, may have a role in forming a depressive episode, yet it remains unclear which properties of temporal processing are central to antidepressant response. Production of a short duration oscillates in a circadian manner. Altered circadian organization of physiology and behavior are a hallmark of bipolar disorder. We thus tested whether circadian dynamics of time production associate with treatment response in bipolar disorder. METHODS: Over the three cycles of total sleep deprivation combined with light therapy (chronotherapeutics) in one week, 20 inpatients with a major depressive episode in the course of bipolar disorder produced 10 s and rated their subjective mood and vigilance levels repeatedly. RESULTS: Eleven patients (58%) among 19 completers achieved remission. Produced time intervals (PTIs) fluctuated more synchronously with mood levels (r = -0.77) than vigilance levels (r = -0.59) during treatment. A higher degree of shortening of PTIs, but not changes in mood or vigilance levels, during the initial 24-h period of treatment predicted better response (LR χ2 = 4.58, P = 0.032). Strong opposite daily changes for PTIs and mood levels observed at baseline were both attenuated after treatment only in remitters (F = 7.25, P = 0.015). LIMITATIONS: Potential external confounders that affect time perception were not controlled. CONCLUSIONS: The results are the first to demonstrate an association of the circadian properties of time perception with antidepressant effects of chronotherapeutics and suggest the potential utility of time production in predicting clinical outcome of bipolar depression.

Antiepileptic drug-induced psychosis associated with MTHFR C677T: a case report.

BACKGROUND: Various antiepileptic drugs can potentially cause psychiatric side effects in patients with epilepsy, but the precise mechanism of these actions remains unknown. In recent years, the common polymorphism C677T in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has attracted attention for its role in the onset of psychiatric diseases. MTHFR and several vitamins (as cofactors) are crucial for remethylation of homocysteine via folate and homocysteine metabolism. We report a case of a Japanese patient who presented with reversible schizophrenia-like symptoms during antiepileptic drug therapy. CASE PRESENTATION: Our patient had frontal lobe epilepsy and had been treated with several antiepileptic drugs since the age of 13 years. He developed auditory hallucinations and multiple personalities at 17 years of age, several months after the initiation of phenytoin and phenobarbital, despite these antiepileptic drugs being used within the therapeutic ranges. Genetic analysis revealed that he was homozygous for the C677T polymorphism of MTHFR. Hyperhomocysteinemia, hypomethionemia, and multiple vitamin deficiencies, including folate, riboflavin, and pyridoxal, were identified at the age of 23 years. Vitamin supplementation and alteration of the antiepileptic drugs improved his psychotic symptoms. Multiple vitamin deficiencies with homozygous MTHFR C677T should be considered in patients presenting with schizophrenia-like symptoms during antiepileptic drug therapy. CONCLUSIONS: To the best of our knowledge, this is the first report of antiepileptic drug-induced psychosis associated with homozygous C677T and multiple vitamin deficiencies. Our findings will contribute to the elucidation of the pathogenesis of the psychiatric side effects of antiepileptic drugs and lead to improved medical management for patients with epilepsy.

Effects of bright light exposure on human fear conditioning, extinction, and associated prefrontal activation.

Bright light (BL) not only regulates human emotion and circadian physiology but can also directly modulate emotional memories. Impaired fear extinction and enhanced fear acquisition and consolidation are hallmarks of fear-circuitry disorders; thus, we tested whether BL facilitates fear extinction and inhibits fear acquisition. We randomly exposed 29 healthy humans to high- (9000 lx) or low-intensity light (<500 lx) for 15 min, near the nadir of the phase response to light, in a single-blind manner. Simultaneously with the light exposure, subjects performed fear extinction training and second fear acquisition, where a visual conditioned stimulus (CS), previously paired with an electric shock unconditioned stimulus (US), was presented without the US, while another CS was newly paired with the US. Conditioned responses (CRs) and changes in prefrontal cortex (PFC) activity were determined during encoding and delayed recall sessions. BL-exposed subjects exhibited lower extinction-related PFC activity and marginally higher acquisition-related PFC activity during light exposure than subjects exposed to control light. Twenty-four hours later, BL reduced CRs to both the extinguished and non-extinguished CSs with marginally lower extinction-related PFC activation, suggesting that BL enhanced fear extinction, while suppressing fear acquisition. Further, BL sustained tolerance to fear re-conditioning. Our results demonstrate that a single and brief BL exposure, synchronized with fear extinction and acquisition, instantaneously influences prefrontal hemodynamic responses and alleviates fear expression after 24 h. Although the specificity of BL effects deems further investigation, our findings indicate the clinical relevance of adjunctive BL intervention in exposure-based cognitive-behavioral therapy for fear-circuitry disorders.

Association of different neural processes during different emotional perceptions of white noise and pure tone auditory stimuli.

Sound is a sensory stimulant ubiquitously found throughout our environment. Humans have evolved a system that effectively and automatically converts sound sensory inputs into emotions. Although different emotional responses to sounds with different frequency characteristics are empirically recognized, there is a paucity of studies addressing different emotional responses to these sounds and the underlying neural mechanisms. In this study, we examined effects of pure tone (PT) and white noise (WN) inputs at ordinary loudness levels on emotional responses. We found that WN stimuli produced more aversive responses than PT stimuli. This difference was endorsed by larger late posterior positivity (LPP). In a source localization study, we found increased neural activity in the parietal lobe prior to LPP. These findings show that WN stimuli produce aversive perceptions compared with PT stimuli, at typical loudness levels. In addition, different emotional responses were processed in a similar manner as visual stimulations, as reflected by increased LPP activation. Various emotional effects of WN and PT stimuli, at ordinary loudness levels, could expand our understanding of adverse effects of noise as well as favorable effects associated with music.

[Diagnosis and treatment in circadian rhythm sleep disorders].

Circadian rhythm sleep disorders (CRSD) are characterized by misalignment between major sleep episode and desired sleep phase, or symptoms associated with internal desynchronization between endogenous circadian rhythm and overt sleep-wake rhythm. Endogenous circadian rhythm is mainly regulated by master circadian clock located in the suprachiasmatic nucleus. Light entrains the circadian clock according to a phase-response curve. Furthermore, social time cue affects human sleep-wake rhythm. Instructions concerning sleep hygiene including light environment play fundamental role for the treatment in CRSD. In addition, light therapy and oral melatonin administration have application to delayed sleep phase type. Diagnostic classification and treatment in each types of CRSD are reviewed in this article.

Reduced intracellular pH in the basal ganglia and whole brain measured by 31P-MRS in bipolar disorder.

The authors have previously reported that intracellular pH measured by phosphorus-31 magnetic resonance spectroscopy (31P-MRS) was decreased in the frontal lobes of patients with bipolar disorder. In the present study, phosphorus metabolism in the basal ganglia was examined in 13 patients with bipolar disorder and 10 matched controls by localized 31P-MRS. While no significant alteration of peak area ratios was found for all phosphorus metabolites, intracellular pH was significantly reduced in the basal ganglia in patients with bipolar disorder (7.014 +/- 0.045) compared with control subjects (7.066 +/- 0.047, P < 0.05). Unexpectedly, non-localized 31P-MR spectra also showed significantly lower levels of intracellular pH (6.970 +/- 0.025) than controls (6.986 +/- 0.024, P < 0.05). These results suggest that decreased intracellular pH in the brain of patients with bipolar disorder is not caused by dysfunction of the frontal lobes but reflect altered metabolism at the cellular level.